Fibroblast growth factor homologous factors (FHFs) are intracellular neuromodulators whose mechanisms of action are still poorly understood. Mice bearing deletions in Fhf genes display neurological deficits associated with motor function, although the animals show no detectable histological or immunohistochemical abnormalities. FHFs are believed to exert their effects through identified binding partners, which include voltage-gated sodium channels. Recent findings from the P.I.'s lab show that FHFs are required for proper intrinsic excitability of neurons, and that FHF-deficient neurons show aberrant voltage-dependent sodium channel behavior. Further data show that FHFs are required for optimal conduction of action potentials along motor axons. In light of these findings, this application proposes experiments to answer four related questions concerning FHF physiology: I. Do FHFs modulate neuronal excitability through direct FHF-sodium channel interactions? II. Are different FHF genes and protein isoforms equivalent or distinct in terms of sodium channel modulation and excitability? III. Does temporal regulation of FHF protein levels contribute to plasticity of intrinsic excitability? IV. Do FHF protein levels impact on the functional severity of demyelination syndromes? These experiments are expected to more fully define the mechanisms and conditions by which FHFs control physiology and pathophysiology of the central nervous system. More specifically, these studies will analyze FHF genes as potential contributors to severity of Charcot-Marie-Tooth syndrome and diabetic peripheral neuropathy, the latter of which constitutes a significant minority health disparity.